Pancreatic endocrine disorders and multiple endocrine neoplasia

Pancreatic neuroendocrine tumours (islet cell tumours) are rare and usually sporadic, but they may be associated with complex familial endocrine cancer syndromes. Recognized types of pancreatic neuroendocrine tumours are those that are nonfunctioning (often advanced at diagnosis due to the absence of symptoms attributable to hormone hypersecretion), insulinoma (the most frequent type, see Chapter 13.11.2), and others including:

Gastrinoma—90% located in the pancreatic region; present with severe, multiple peptic ulcers that are often associated with complications such as haemorrhage, perforation, and stricture formation (Zollinger–Ellison syndrome); diagnosis requires demonstration of a raised fasting plasma gastrin concentration associated with increased basal gastric acid secretion; symptomatic treatment is with high-dose proton pump inhibitors.

VIPoma—90% occur in the pancreas; present with large-volume diarrhoea without steatorrhoea (Verner–Morrison syndrome, pancreatic cholera); hypokalaemia may be profound; diagnosis can be confirmed by finding of an elevated plasma level of peptide histidine–methionine (PHM, produced from the prepro-VIP molecule); diarrhoea responds well to somatostatin analogues (octreotide, lanreotide).

Glucagonoma—rare α-cell tumours of the pancreas; presenting features include weight loss, diarrhoea, anorexia, abdominal discomfort (hepatomegaly from metastases), and diabetes, also necrolytic migratory erythema; diagnosis is made on the basis of an elevated fasting plasma glucagon in association with characteristic clinical features; skin rash and other symptoms may respond to somatostatin analogues; oral zinc sulphate supplementation may be of benefit and is usually given.

Management—the following should be considered in addition to the symptomatic treatments for pancreatic neuroendocrine tumours described: (1) surgical resection—the only curative treatment, but not possible in many cases; (2) systemic chemotherapy, with recent focus on agents which inhibit specific kinases involved in tumour cell proliferation, growth, and angiogenesis; (3) radiopharmaceutical therapy (radiolabelled somatostatin analogues).

Multiple endocrine neoplasia (MEN)

There are two main MEN syndromes, which are rare hereditary conditions characterized by a predisposition to cancer development within two or more endocrine organs.

MEN 1—typical features are parathyroid adenomas, pancreatic neuroendocrine tumours (gastrinomas > insulinomas > others) and pituitary adenomas; caused by mutation of the MEN1 gene, which encodes a nuclear protein (menin) that is presumed to be a tumour suppressor gene, with diagnosis confirmed by genetic analysis; following identification of an index case, genetic analysis in first-degree relatives allows identification of affected family members; minimal surveillance programme for individuals with MEN1 syndrome or a family-specific mutation of the MEN1 gene should include annual measurement of serum prolactin (from age 5 years), fasting serum calcium and PTH (from age 8 years), and fasting serum gastrin concentration (from age 20 years).

MEN 2—there are three variants: (1) MEN 2A (Sipple’s syndrome)—medullary thyroid carcinoma, phaeochromocytoma, and parathyroid hyperplasia/adenomas; (2) MEN 2B—medullary thyroid carcinoma and phaeochromocytoma, with other features including marfanoid habitus and mucosal neuromas; (3) familial medullary thyroid carcinoma. Caused by mutation in the RET oncogene, with diagnosis confirmed by genetic analysis and strong genotype–phenotype correlation informing management of index cases and affected family members, e.g. prophylactic thyroidectomy is recommended for those with mutations conferring the highest risk of aggressive medullary thyroid carcinoma; annual measurement of urinary catecholamines for those with high risk of phaeochromocytoma.

Other syndromes of MEN include (1) Carney complex, (2) McCune–Albright syndrome, (3) neurofibromatosis type 1, (4) von Hippel–Lindau syndrome.